Viruses are the etiologic cause of many life-threatening human diseases. Of special importance are herpes viruses such as herpes simplex 1 (HSV-1), herpes simplex 2 (HSV-2), cytomegalovirus (CMV), Epstein-Barr virus (EBV), varicella zoster virus (VZV) and human herpes virus 6 (HHV 6) which are associated with many common viral illnesses. The HSV-1 and HSV-2 infections are characterized by cold sores of skin, mouth or genital region. After primary infection the virus is harbored in neural cells and can reappear later in the life of a patient. Human CMV (HCMV) infection is a life-long affliction which can result in morbidity and mortality. These pathologies include microcephaly, hepatosplenomegaly, jaundice, encephalitis, infections of the newborn infants or fetuses in utero, and infections of immunocompromised hosts. The HCMV infection is responsible for retinitis, gastritis and pneumonitis in AIDS patients and HCMV-induced pneumonias or hepatitis are frequent and serious complications of bone marrow transplants. EBV causes infectious mononucleosis and it is considered as the etiologic agent of nasopharyngeal cancer, immunoblastic lymphoma, Burkitt's lymphoma and hairy leukoplakia. VZV causes chicken pox and shingles. Although in children the chicken pox is usually a non-fatal disease, the recurrent form of this infection, shingles, may in advanced stage lead to paralysis, convulsions and ultimately death. Again, in immunocompromised patients the infection with VZV is a serious complication. Human herpes virus 6 (HHV-6) which is commonly associated with children's rash was also identified in acquired immunodeficiency syndrome (AIDS) patients and it may be a cofactor in the pathogenesis of AIDS in hosts infected with human immunodeficiency virus (HIV). Levine, A. J., Viruses, Ch. 4, W. H. Freeman & Co., New York, pp. 67-85 (1992); Human Herpesvirus Infections, Raven Press, New York (1986).
HIV is the underlying cause of AIDS, a world-wide epidemic with fatal consequences. According to the World Health Organization, over 4.5 million AIDS cases were recorded by late 1994 and 19.5 million people had been infected with HIV. It is estimated that by the year 2000, 30 to 40 million will have been infected with HIV with 10 million cases of full-blown AIDS. Estimates of Global AIDS Policy Coalition are considerably higher—up to 110 million HIV infections and 25 million AIDS cases. The Relationship between the Human Immunodeficiency Virus and the Acquired Immunodeficiency Syndrome, The National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md., pp. 1-3 (1995).
Various alkyl derivatives of purines and pyrimidines and analogues thereof have been found to exhibit antiviral activity. Notably, acyclovir (Zovirax) and ganciclovir (Cytovene) belonging to this group of compounds are approved drugs for infections caused by HSV-1, HSV-2, VZV and HCMV. Acyclovir Therapy for Herpesvirus Infections (Baker, Ed.), M. Dekker, New York, (1990); Ganciclovir Therapy for Cytomegalovirus Infection (Spector, S. S., Ed.), M. Dekker, New York (1991). A considerable effort went into design, synthesis and biological investigation of analogues of these drugs as well as in development of new antiviral agents. Larsson, A., et al., Antimicrob. Agents & Chemother. 30:598-605 (1986); Ashton, W. T., et al., J. Med. Chem. 31:2304-2315 (1988).
Current drugs for AIDS include AZT (zidovudine, Retrovir), ddI (didanosine, Videx), ddC (zalcitabine, Hivid) and d4T (stavudine, Zerit). De Clercq, E., J. Med. Chem. 38:2491-2517 (1995). Allenic nucleoside analogues such as adenallene and cytallene are examples of anti-HIV agents containing an unsaturated alkyl group. U.S. Pat. No. 4,935,427; Zemlicka, J., Allenols Derived from Nucleic Acid Bases—a New Class of Anti-HIV Agents: Chemistry and Biological Activity in Nucleosides and Nucleotides as Antitumor and Antiviral Agents (Chu, C. K.; Baker, D. C., Eds.), Plenum Press, New York, pp. 73-100 (1993).
It would thus be desirable to provide novel compounds which are active against viruses, including HCMV, HSV-1, HSV-2, HHV-6, HIV, hepatitis B virus (HBV), and other mammalian viruses.